Activated Charcoal and Bicarbonate for Aspirin Toxicity: a Retrospective Series.

INTRODUCTION: Aspirin overdose causes acid-base disturbances and organ dysfunction. Management is guided by research reported over 50 years ago when chronic aspirin toxicity was common and accounted for significant morbidity. We investigate our experience of aspirin overdose and the effectiveness of charcoal and bicarbonate administration over 20 years. METHODS: This is a retrospective series of acute aspirin overdose from two toxicology units from January 2000 to September 2019. Acute aspirin ingestions > 3000 mg were identified in each unit's database. Excluded were cases of chronic exposure, hospital presentation > 24 hours after ingestion, and cases without a salicylate concentration. Included in our analysis was demographic data, clinical effects, investigations, complications, and treatment. RESULTS: There were 132 presentations in 108 patients (79 females (73%)). The median age was 28 years (range: 13-93 years). The median dose ingested was 7750 mg (IQR: 6000-14,400 mg). There were 44 aspirin-only ingestions. Mild toxicity (nausea, vomiting, tinnitus or hyperventilation) occurred in 22 with a median dose of 160 mg/kg. Moderate toxicity (acid-base disturbance, confusion) occurred in 16 with a median ingested dose of 297 mg/kg. There were no cases of severe toxicity (coma or seizures) due to aspirin alone. The median peak salicylate concentration was 276 mg/L (IQR: 175-400 mg/L, range: 14-814 mg/L). There was a moderate association between dose ingested and peak concentration (Pearson r = 0.58; 95% CI 0.45-0.68). Activated charcoal was administered in 36 (27%) cases, which decreased the median peak salicylate concentration (34.2 to 24.8 mg/L/g (difference: 9.4, 95% CI: 1.0-13.1)). Bicarbonate was administered in 34 (26%) presentations, decreasing the median apparent elimination half-life from 13.4 to 9.3 h (difference: 4.2 h, 95% CI: 1.0-6.5 h). CONCLUSIONS: Acute aspirin overdose caused only mild to moderate effects in this series. Early administration of activated charcoal decreased absorption and use of bicarbonate enhanced elimination.

Life-threatening triclopyr poisoning due to diethylene glycol monoethyl ether solvent.

INTRODUCTION: Triclopyr is a synthetic auxin-like herbicide. It is considered to have low toxicity and there are few reports of poisoning. We report two cases of life-threatening toxicity following ingestions of 250 mL of 50 g/L triclopyr co-formulated with diethylene glycol monoethyl ether (DEGEE). CASE REPORTS: A 79-year-old male with a background of hypertension and atrial fibrillation presented two hours after ingestion with sedation, a severe high anion gap metabolic acidosis, raised osmolar gap and an aspiration pneumonitis. He was ventilated and dialysed for 10 h with resolution of the acidaemia. He was discharged home on day 33. A 66-year-old male with a past history of alcoholism and hypertension presented following a collapse. He had sedation, a severe high anion gap metabolic acidosis with a raised osmolar gap, acute kidney injury and vasodilatory shock. He was ventilated and received dialysis for 43 h. He had poor neurological recovery and died on day 10. DISCUSSION: Ingestion of triclopyr formulations can produce life-threatening toxicity. In large poisonings of triclopyr co-formulated with DEGEE, a high anion gap metabolic acidosis appears to be due to the glycol ether solvent rather than triclopyr itself. Management should focus on good supportive care including dialysis for significant metabolic acidosis.

A randomized controlled trial of fresh frozen plasma for coagulopathy in Russell's viper (Daboia russelii) envenoming.

Essentials Russell's viper envenoming is a major health issue in South Asia and causes coagulopathy. We studied the effect of fresh frozen plasma and two antivenom doses on correcting coagulopathy. Fresh frozen plasma did not hasten recovery of coagulopathy. Low-dose antivenom did not worsen coagulopathy. SUMMARY: Background Russell's viper (Daboia russelii) envenoming is a major health issue in South Asia and causes venom-induced consumption coagulopathy (VICC). Objectives To investigate the effects of fresh frozen plasma (FFP) and two antivenom doses in correcting VICC. Methods We undertook an open-label randomized controlled trial in patients with VICC at two Sri Lankan hospitals. Patients with suspected Russell's viper bites and coagulopathy were randomly allocated (1 : 1) to high-dose antivenom (20 vials) or low-dose antivenom (10 vials) plus 4 U of FFP. The primary outcome was the proportion of patients with an International Normalized Ratio (INR) of < 2 at 6 h after antivenom administration. Secondary outcomes included anaphylaxis, major hemorrhage, death, and clotting factor recovery. Results From 214 eligible patients, 141 were randomized: 71 to high-dose antivenom, and 70 to low-dose antivenom/FFP; five had no post-antivenom blood tests. The groups were similar except for a delay of 1 h in antivenom administration for FFP patients. Six hours after antivenom administration, 23 of 69 (33%) patients allocated to high-dose antivenom had an INR of < 2, as compared with 28 of 67 (42%) allocated to low-dose antivenom/FFP (absolute difference 8%; 95% confidence interval - 8% to 25%). Fifteen patients allocated to FFP did not receive it. Severe anaphylaxis occurred equally frequently in each group. One patient given FFP developed transfusion-related acute lung injury. Three deaths occurred in low-dose antivenom/FFP patients, including one intracranial hemorrhage. There was no difference in recovery rates of INR or fibrinogen, but there was more rapid initial recovery of factor V and FX in FFP patients. Conclusion FFP after antivenom administration in patients with Russell's viper bites did not hasten recovery of coagulopathy. Low-dose antivenom/FFP did not worsen VICC, suggesting that low-dose antivenom is sufficient.

Severe Hypertension and Bradycardia Secondary to Midodrine Overdose.

The objective of this case is to describe the pharmacokinetics and toxicity of midodrine in overdose. A 20 year old female ingested up to 350 mg midodrine while recovering in hospital from another overdose. She developed vomiting and severe hypertension (blood pressure [BP], 210/100 mmHg). Remarkable findings included a heart rate with a range of 43-60 beats/min, spontaneous respirations (20 breaths/min), and oxygen saturations of >95 % on FiO2 25 %, and a GS of 8. She was admitted to intensive care and had a normal non-contrast CT brain. She was treated with a glyceryl trinitrate patch (5 mg) and observed for 36 h with subsequent BP reduction to 124/81 mmHg and improved in conscious state. Midodrine and desglymidodrine concentrations were measured with liquid chromatography tandem mass spectrometry and were detected with 2-h post-ingestion at concentrations of 158.4 and 169.7 ng/mL, respectively. The parent drug concentrations rapidly decreased with an elimination of half-life of 1.6 h, and the metabolite initially increased and then decreased. The peak in blood pressure appeared to coincide with peak metabolite concentrations. Midodrine in overdose can potentially cause severe hypertension and reflex bradycardia but given its short half-life treatment with vasodilator agents and supportive care is sufficient.

Desvenlafaxine overdose and the occurrence of serotonin toxicity, seizures and cardiovascular effects.

CONTEXT: Desvenlafaxine is used to treat major depression. Desvenlafaxine is also the active metabolite of venlafaxine. Venlafaxine overdose can cause serotonin toxicity, seizures and cardiovascular effects, but there is limited information on desvenlafaxine overdose. OBJECTIVE: We aimed at investigating the clinical effects and complications from desvenlafaxine overdose. MATERIALS AND METHODS: This was a retrospective observational study of desvenlafaxine overdoses over a six-year period. Demographic details, dose and timing of the overdose, together with clinical effects, treatment and complications were extracted from a local hospital network database or the medical records of patients following hospital admission with a desvenlafaxine overdose. RESULTS: There were 182 cases of desvenlafaxine overdose included in the study. From the 182 cases, 75 were desvenlafaxine (± alcohol) only ingestions and 107 included one or more co-ingested drugs. In single-agent desvenlafaxine ingestions, median age was 25 years (range: 13-68 years) with a median ingested dose of 800 mg (range: 250-3500 mg; interquartile range (IQR): 600-1400 mg), and 54/75 (72%) were female. The Glasgow Coma Score (GCS) was 15 in 68/74 (92%) patients, 13-14 in 5/74 (7%), and was seven in one patient following aspiration. Mild hypertension (systolic blood pressure [BP] > 140-180 mmHg) occurred in 23/71 patients (32%), and tachycardia occurred in 29/74 (39%) patients. There were no abnormal QT intervals and no QRS >120 m s. Serotonin toxicity was diagnosed by the treating physician in 7/75 (9%) patients, but only one of these met the Hunter Serotonin Toxicity Criteria. None of the 75 patients who took desvenlafaxine only (± alcohol) had seizures, were admitted to intensive care or died. In comparison, the 107 patients taking desvenlafaxine in overdose with other medications developed more pronounced toxicity. Generalised seizures occurred in 5/107 (5%), but in three of these cases co-ingestants were possible proconvulsants. Fifteen patients had a GCS ≤9 and none had an abnormal QT or QRS. Severe effects appeared to be associated with coingestants. CONCLUSION: Desvenlafaxine overdose causes minor effects with mild hypertension and tachycardia. The risk of seizures or serotonin toxicity is low.

Hyperlactataemia and clinical severity of acute metformin overdose.

BACKGROUND: Although metformin-associated lactic acidosis is well described, there is less information on metformin overdose and whether it is of similar severity. AIMS: This study aims to describe the clinical features, laboratory investigations and outcome of acute metformin overdoses. METHODS: Retrospective case series of acute metformin overdoses (> 3 g) admitted to a toxicology unit over 20 years. Cases were identified from a prospective database and data extracted included demographics, dose, coingestants, clinical effects, investigations, treatment and outcomes. RESULTS: There were 36 acute metformin overdose cases. Median age 41 years old (15-68 years old); 25 were female. Median ingested dose was 10 g (interquartile range (IQR): 5-16.1 g; range: 3.5-50 g), with coingestants taken in 34 presentations. Gastrointestinal symptoms were present in 12/36, tachycardia in 10, bradycardia in three, hypotension in four and hypoglycaemia in eight. Hypotension and bradycardia were consistent with coingestants taken. Blood pH and lactate levels were available in 25/36. Median lowest pH was 7.35 (IQR: 7.28-7.38) and acidosis (pH < 7.35) occurred in 11/25. Median peak lactate was 3.9 mmol/L (IQR: 2.6-5.2 mmol/L). There was a statistical association between dose and lactate (r = 0.51; P = 0.01) and dose and pH (r = -0.70; P = 0.0001). Hyperlactataemia (lactate > 2 mmol/L) without acidosis occurred in 10/25, and hyperlactataemia with acidosis in 11/25; five had lactic acidosis. The median time to peak lactate in 10 presentations with peak lactate > 2 was 6 h (2-19 h). There were six intensive care unit admissions, one for lactic acidosis, and five related to coingestants. There were no deaths. CONCLUSION: Metformin overdose is characterised by hyperlactataemia and minor gastrointestinal effects, with a few large ingestions progressing to lactic acidosis. Coingestants are common and may dominate toxicity.

Antivenom cross neutralisation in a suspected Asian pit viper envenoming causing severe coagulopathy.

There is evidence of cross-neutralisation between common toxin groups in snake venoms and therefore the potential for antivenoms to be effective against species they are not raised against. Here we present a 49 year old female bitten by an unknown pit-viper in Nepal. She developed a venom induced consumption coagulopathy with an unrecordable international normalised ratio and undetectable fibrinogen. On return to Australia 5 days post-bite she was treated successfully with one antivenom raised against Malayan pit viper and green pit viper venoms (Haemato-polvalent antivenom from Thailand) and then subsequently with another antivenom raised against American pit-viper venoms (Antivipmyn). Presumed pit viper venom was detected in patient sera with an enzyme immunoassay against Hypnale hypnale venom. There was increased absorbance before antivenom compared to non-envenomed control samples, which then decreased after the administration of each antivenom. The recurrence of venom detected by enzyme immunoassay between antivenom doses was accompanied by a recurrence of the coagulopathy. Cross reactivity between the unknown venom and both antivenoms was supported by the fact that no venom was detected in the pre-antivenom samples after they were incubated in vitro with both antivenoms. This case and investigation of the venom and antivenoms suggest cross-neutralisation between pit vipers, including pit vipers from different continents.

Pharmacokinetics and pharmacodynamics of the myotoxic venom of Pseudechis australis (mulga snake) in the anesthetised rat.

CONTEXT: Myotoxicity is a common clinical effect of snake envenoming and results from either local or systemic myotoxins in snake venoms. Although numerous myotoxins have been isolated from snake venoms, there has been limited study on the relationship between the time course of venom concentrations (pharmacokinetics) and the time course of muscle injury measured as a rise in creatine kinase (CK) (pharmacodynamics). OBJECTIVE: The aim of this study was to develop an in vivo model of myotoxicity to investigate the time course of myotoxicity and the effect of antivenom. MATERIALS AND METHODS: Anesthetised rats were administered Pseudechis australis (mulga snake) venom either through i.v., i.m. or s.d. route, including a range of doses (5-100 µg/kg). Serial blood samples were collected for measurement of venom using enzyme immunoassay and measurement of CK and creatinine. Antivenom was administered before, 1 and 6 h after venom administration to investigate its effect on muscle injury. Plots of venom and CK versus time were made and the area under the curve (AUC) was calculated. RESULTS: There was a significant dose-dependent increase in CK concentration after administration of P. australis venom, which was greatest for i.v. administration. Timed measurement of venom concentrations showed a rapid absorption through s.d. and i.m. routes and a delayed rise in CK concentrations following any route. Antivenom prevented myotoxicity shown by a decrease in the CK AUC, which was most effective if given earliest. There was a rise in creatinine following i.v. venom administration. CONCLUSION: The study shows the delayed relationship between venom absorption and the rise in CK, consistent with the delayed onset of myotoxicity in human envenoming. Antivenom prevented myotoxicity more effectively if given earlier.

Serotonin toxicity from antidepressant overdose and its association with the T102C polymorphism of the 5-HT2A receptor.

Serotonin toxicity results from serotonin excess in the central nervous system from serotonergic drugs. Previous studies suggest an association between T102C polymorphism of the serotonin 2A (5-hydroxytryptamine 2A) receptor gene and serotonergic adverse effects with serotonergic drugs. We aimed to determine whether there is an association between the T102C polymorphism and serotonin toxicity in patients taking serotonergic drug overdoses. Ninety-five patients presenting with serotonergic drug overdoses were examined for serotonin toxicity and had blood collected for DNA analysis. A diagnosis of serotonin toxicity was made in 14 patients (15%) based on the Hunter Serotonin Toxicology Criteria. Four of the 14 patients (29%) with serotonin toxicity had the C/C genotype compared with 20/81 (25%) without serotonin toxicity. There were no differences in age or sex, but the median defined daily dose taken by patients with serotonin toxicity was 27 (14-84) compared with 18 (2-136) in patients without serotonin toxicity (P=0.06). There was no association between serotonin toxicity and the T102C polymorphism in patients taking a serotonergic drug overdose.

Scale reduction of a systems coagulation model with an application to modeling pharmacokinetic-pharmacodynamic data.

Bridging systems biology and pharmacokinetics-pharmacodynamics has resulted in models that are highly complex and complicated. They usually contain large numbers of states and parameters and describe multiple input-output relationships. Based on any given data set relating to a specific input-output process, it is possible that some states of the system are either less important or have no influence at all. In this study, we explore a simplification of a systems pharmacology model of the coagulation network for use in describing the time course of fibrinogen recovery after a brown snake bite. The technique of proper lumping is used to simplify the 62-state systems model to a 5-state model that describes the brown snake venom-fibrinogen relationship while maintaining an appropriate mechanistic relationship. The simplified 5-state model explains the observed decline and recovery in fibrinogen concentrations well. The techniques used in this study can be applied to other multiscale models.

Detection of venom-antivenom (VAV) immunocomplexes in vitro as a measure of antivenom efficacy.

The measurement of free venom with enzyme immunoassay in serum of patients with snake envenoming is used to confirm snake identification and to determine if sufficient antivenom has been given. Recent studies with Russell's viper (RV; Daboia russelii) envenoming have detected free venom post-antivenom despite recovery of coagulopathy. This raises the question as to whether this assay also measures venom-antivenom (VAV) complexes. In this study we developed an assay to measure VAV complexes and investigate the binding of venom and antivenom in vitro. The assay consisted of rabbit anti-snake venom IgG attached to a microplate which binds the venom component of VAV and anti-horse IgG antibodies conjugated to horseradish peroxidase to detect the antivenom portion of VAV. A known amount of venom or toxin was incubated with increasing antivenom concentrations and VAV was detected as absorbance at 450 nm and plotted against AV concentration. Pseudonaja textilis (brown snake), Notechis scutatus (tiger snake), Oxyuranus scutellatus (taipan), Tropidechis carinatus (rough-scaled snake), Pseudechis porphyriacus (red-bellied black snake) and D. russelii mixtures with appropriate antivenoms were assayed. Measured VAV initially increased with increasing antivenom concentration until it reached a maximum after which the VAV concentration decreased with further increasing antivenom concentrations. The VAV curves for two Australian snake venom-antivenom mixtures, Hoplocephalus stephensii and Ancanthophis antarcticus, had broad VAV peaks with two maxima. Two fractions isolated from N. scutatus venom and Russell's viper factor X activator toxin produced similar VAV curves to their whole venoms. The antivenom concentration for which the maximum VAV occurred was linearly related to the venom concentration, and this slope or ratio was consistent with that used to define the neutralisation units for Australian antivenoms. The maximal VAV point appears to represent the antivenom concentration where every venom molecule (toxin) is attached to at least one antivenom molecule (antibody) on average and may be a useful measure of antivenom efficacy. In vivo this would mean that for a defined antivenom concentration, venom components will be eliminated and are trapped in the central compartment.

Mirtazapine overdose is unlikely to cause major toxicity.

OBJECTIVE: There is limited information on mirtazapine overdose, but cases of severe effects (seizures, serotonin toxicity and coma) have been reported. We aimed to investigate the clinical effects and complications of mirtazapine overdose. METHODS: This was an observational case series of mirtazapine overdoses (> 120 mg) identified from admissions to a toxicology unit between January 1987 and August 2013. Demographic information, details of ingestion, clinical effects, ECG parameters (HR, QT and QRS), and length of stay were extracted from a clinical database. RESULTS: From 267 mirtazapine overdoses, there were 89 single-agent mirtazapine ingestions and 178 cases where mirtazapine was taken with at least one other drug. The median age of the 89 single-agent mirtazapine ingestions was 36 years [interquartile range (IQR): 26-49 years; Range: 15-81 years]; 45 were female (51%). The median ingested dose was 420 mg (IQR: 270-750 mg; Range: 150-1350 mg) and 41 patients (46%) had a Glasgow coma score (GCS) < 15, but the minimum GCS was 10. There were no seizures, serotonin toxicity or delirium. Tachycardia occurred in 29 patients (33%) and hypertension in 32 patients (36%). The median QRS was 80 ms (Range: 80-120 ms) and there were no cases with QT prolongation. There were no arrhythmias and no deaths. The median length of stay was 14 h (IQR: 8.8-18.2 h; Range:2.2-75 h). No single-agent mirtazapine patient was admitted to intensive care. The 178 patients taking co-ingestants had more severe toxicity depending on the co-ingested drug. CONCLUSION: Mirtazapine appears to be relatively benign in overdose, associated with tachycardia, mild hypertension and mild CNS depression not requiring intervention.

Predicting the requirement for N-acetylcysteine in paracetamol poisoning from reported dose.

CONTEXT: There is contention over whether reported dose correlates with toxicity in paracetamol poisoning and risk assessment is currently based on serum paracetamol concentration compared to a nomogram, irrespective of reported dose. Objective. To determine if reported dose predicts the need for N-acetylcysteine (NAC). METHODS: Data were taken from paracetamol overdoses presenting to a tertiary toxicology service. Age, sex, reported dose, ingestion time, timed paracetamol concentrations between 4 and 16 h, hepatotoxicity (peak alanine transaminase > 1000 U/L) and treatment (single dose-activated charcoal [SDAC] and NAC) were analysed. Data were analysed within a repeated measures logistic regression framework using NONMEM (ver 7.2). The primary outcome was administration of NAC, which was determined based on a serum paracetamol concentration greater than the nomogram line. RESULT: There were 1571 admissions in 1303 patients, with a median age of 27 years (12-96 years) and 1140 (73%) were females. The median dose was 10 g (1-100 g). The paracetamol concentration was above the nomogram line in 337 of 1571 (22%) patients. Patients presenting later (first paracetamol concentration between 7 and 16 h post-overdose) compared to those presenting earlier (4-7 h post-overdose) were more likely to have hepatotoxicity (5.5% vs. 0.4%; p < 0.0001), have a toxic paracetamol concentration (34% vs. 18%; p < 0.0001) and receive NAC (48% vs. 23%; p < 0.0001). SDAC reduced the probability of the paracetamol concentration being above the nomogram. Based on SDAC not being administered there was a 5% probability of requiring NAC at a dose of 6-9 g, a 10% chance of requiring NAC at a dose of 13-16 g, a 50% chance of requiring NAC at a dose of 30-34 g and a 90% chance for needing NAC at 48-50 g. CONCLUSION: Reported dose was a good predictor of a toxic paracetamol concentration and SDAC reduced the probability of the concentration being above the nomogram. These predictions may assist in determining which patients could be started on NAC immediately.

Hump-nosed pit viper (Hypnale hypnale) envenoming causes mild coagulopathy with incomplete clotting factor consumption.

CONTEXT: Limited information exists on the coagulopathy caused by hump-nosed pit viper (Hypnale hypnale) envenoming. OBJECTIVES: This study aimed to characterise the coagulopathy in hump-nosed pit viper bites by measuring laboratory clotting times and factor studies. MATERIALS AND METHODS: Cases of hump-nosed pit viper envenoming were included from a prospective cohort study of Sri Lankan snake-bite patients. Patient age, sex, snake identification, time of bite and clinical effects were recorded. Patients did not receive anti-venom because no specific anti-venom to hump-nosed vipers exists. All patients received supportive care and serial 20-min whole blood clotting tests (WBCT20). The prothrombin time (PT), international normalised ratio (INR), activated partial thromboplastin time (aPTT), coagulation factors I, II, V, VII, VIII, IX and X, von Willebrand factor (vWF) antigen and D-Dimer concentrations were measured. The median of highest or lowest test result for each patient was reported with interquartile range (IQR). Results. There were 80 hump-nosed pit viper bites, median age was 37 years (IQR: 26-51 years) and 48 were male. The WBCT20 was positive in one patient. The median highest INR was 1.9 (1.5-2.2; Range: 1.3 to > 12) and median highest aPTT was 54 s (46-72 s; Range: 35-170 s). There was low fibrinogen [median: 1.3 g/L;1, -1.8 g/L; Range: < 0.2-2.9], low factor VIII levels [median: 23%; 16-37%] and low factor V levels [median: 43%; 23-74%]. D-Dimer concentrations [median: 3.4 mg/L; 2-7.4 mg/L] were slightly elevated. Factors II, VII and X and vWF antigen concentrations were normal. DISCUSSION AND CONCLUSIONS: Hump-nosed pit viper bites result in a mild coagulopathy which is usually not detected by a WBCT20. It is characterised by mild elevation of INR, low fibrinogen and Factors V and VIII which may be consistent with the venom containing a thrombin-like enzyme.

Diagnostic 20-min whole blood clotting test in Russell's viper envenoming delays antivenom administration.

BACKGROUND: The 20-min whole blood clotting test (WBCT20) is widely used for the identification of coagulopathy in snake envenoming, but its performance in practice has not been evaluated. AIM: We aimed to investigate the diagnostic utility of the WBCT20 for coagulopathy in Russell's viper envenoming. DESIGN: Prospective observational study. METHODS: Adult patients with snake envenoming were recruited. Age, sex, bite information, clinical effects, serial WBCT20 and antivenom treatment were recorded. Definite Russell's viper envenoming was confirmed with venom specific enzyme immunoassay. We assessed sensitivity of admission WBCT20 to coagulopathy (international normalized ratio, INR > 1.5) in Russell's viper envenoming, the specificity of negative WBCT20 in non-envenomed patients and directly compared paired WBCT20 and INR. RESULTS: Admission WBCT20 was done in 140 Russell's viper bites with coagulopathy and was positive in 56/140 [sensitivity 40% (95% confidence interval (CI): 32-49%)]. A negative WBCT20 led to delayed antivenom administration [WBCT20-ve tests: median delay, 1.78 h (interquartile range (IQR): 0.83-3.7 h) vs. WBCT20 + ve tests: median delay, 0.82 h (IQR: 0.58-1.48 h); P = 0.0007]. Delays to antivenom were largely a consequence of further WBCT20 being performed and more common if the first test was negative (41/84 vs. 12/56). Initial WBCT20 was negative in 9 non-envenomed patients and 48 non-venomous snakebites [specificity: 100% (95% CI: 94-100%)]. In 221 paired tests with INR > 1.5, the WBCT20 was positive in 91(41%). The proportion of positive WBCT20 only increased slightly with higher INR. CONCLUSION: In clinical practice, the WBCT20 has low sensitivity for detecting coagulopathy in snake envenoming and should not over-ride clinical assessment-based decisions about antivenom administration. There is an urgent need to develop a simple bedside test for coagulopathy in snake envenoming.

Mulga snake (Pseudechis australis) envenoming: a spectrum of myotoxicity, anticoagulant coagulopathy, haemolysis and the role of early antivenom therapy - Australian Snakebite Project (ASP-19).

CONTEXT: Mulga snakes (Pseudechis australis) are venomous snakes with a wide distribution in Australia. Objective. The objective of this study was to describe mulga snake envenoming and the response of envenoming to antivenom therapy. MATERIALS AND METHODS: Definite mulga bites, based on expert identification or venom-specific enzyme immunoassay, were recruited from the Australian Snakebite Project. Demographics, information about the bite, clinical effects, laboratory investigations and antivenom treatment are recorded for all patients. Blood samples are collected to measure the serum venom concentrations pre- and post-antivenom therapy using enzyme immunoassay. RESULTS: There were 17 patients with definite mulga snake bites. The median age was 37 years (6-70 years); 16 were male and six were snake handlers. Thirteen patients had systemic envenoming with non-specific systemic symptoms (11), anticoagulant coagulopathy (10), myotoxicity (7) and haemolysis (6). Antivenom was given to ten patients; the median dose was one vial (range, one-three vials). Three patients had systemic hypersensitivity reactions post-antivenom. Antivenom reversed the coagulopathy in all cases. Antivenom appeared to prevent myotoxicity in three patients with high venom concentrations, given antivenom within 2 h of the bite. Median peak venom concentration in 12 envenomed patients with samples was 29 ng/mL (range, 0.6-624 ng/mL). There was a good correlation between venom concentrations and the area under the curve of the creatine kinase for patients receiving antivenom after 2 h. Higher venom concentrations were also associated with coagulopathy and haemolysis. Venom was not detected after antivenom administration except in one patient who had a venom concentration of 8.3 ng/ml after one vial of antivenom, but immediate reversal of the coagulopathy. DISCUSSION: Mulga snake envenoming is characterised by myotoxicity, anticoagulant coagulopathy and haemolysis, and has a spectrum of toxicity that is venom dose dependant. This study supports a dose of one vial of antivenom, given as soon as a systemic envenoming is identified, rather than waiting for the development of myotoxicity.

A randomized controlled trial of fresh frozen plasma for treating venom-induced consumption coagulopathy in cases of Australian snakebite (ASP-18).

BACKGROUND: Venom-induced consumption coagulopathy (VICC) is a major effect of snake envenoming. OBJECTIVES: To investigate whether fresh frozen plasma (FFP) given after antivenom resulted in more rapid correction of coagulation. PATIENTS/METHODS: This was a multicenter open-label randomized controlled trial in patients with VICC of FFP vs. no FFP within 4 h of antivenom administration. Patients (> 2 years) recruited to the Australian snakebite project with VICC (International Normalized Ratio [INR] > 3) were eligible. Patients were randomized 2 : 1 to receive FFP or no FFP. The primary outcome was the proportion with an INR of < 2 at 6 h after antivenom administration. Secondary outcomes included time from antivenom administration to discharge, adverse effects, major hemorrhage, and death. RESULTS: Of 70 eligible patients, 65 consented to be randomized: 41 to FFP, and 24 to no FFP. Six hours after antivenom administration, more patients randomized to FFP had an INR of < 2 (30/41 [73%] vs. 6/24 [25%]; absolute difference, 48%; 95% confidence interval 23-73%; P = 0.0002). The median time from antivenom administration to discharge was similar (34 h, range 14-230 h vs. 39 h, range 14-321 h; P = 0.44). Seven patients developed systemic hypersensitivity reactions after antivenom administration - two mild and one severe (FFP arm), and three mild and one severe (no FFP). One serious adverse event (intracranial hemorrhage and death) occurred in an FFP patient with pre-existing hypertension, who was hypertensive on admission, and developed a headache 6 h after FFP administration. Post hoc analysis showed that the median time from bite to FFP administration was significantly shorter for non-responders to FFP than for responders (4.7 h, interquartile range [IQR] 4.2-6.7 h vs. 7.3 h, IQR 6.1-8 h; P = 0.002). CONCLUSIONS: FFP administration after antivenom administration results in more rapid restoration of clotting function in most patients, but no decrease in discharge time. Early FFP administration (< 6-8 h) post-bite is less likely to be effective.

Use of immunoturbidimetry to detect venom-antivenom binding using snake venoms.

INTRODUCTION: Immunoturbidimetry studies the phenomenon of immunoprecipitation of antigens and antibodies in solution, where there is the formation of large, polymeric insoluble immunocomplexes that increase the turbidity of the solution. We used immunoturbidimetry to investigate the interaction between commercial snake antivenoms and snake venoms, as well as cross-reactivity between different snake venoms. METHODS: Serial dilutions of commercial snake antivenoms (100µl) in water were placed in the wells of a microtitre plate and 100µl of a venom solution (50µg/ml in water) was added. Absorbance readings were taken at 340nm every minute on a BioTek ELx808 plate reader at 37°C. Limits imposed were a 30minute cut-off and 0.004 as the lowest significant maximum increase. Reactions with rabbit antibodies were carried out similarly, except that antibody dilutions were in PBS. RESULTS: Mixing venom and antivenom/antibodies resulted in an immediate increase in turbidity, which either reached a maximum or continued to increase until a 30minute cut-off. There was a peak in absorbance readings for most Australian snake venoms mixed with the corresponding commercial antivenom, except for Pseudonaja textilis venom and brown snake antivenom. There was cross-reactivity between Naja naja venom from Sri Lanka and tiger snake antivenom indicated by turbidity when they were mixed. Mixing rabbit anti-snake antibodies with snake venoms resulted in increasing turbidity, but there was not a peak suggesting the antibodies were not sufficiently concentrated. The absorbance reading at pre-determined concentrations of rabbit antibodies mixed with different venoms was able to quantify the cross-reactivity between venoms. Indian antivenoms from two manufacturers were tested against four Sri Lankan snake venoms (Daboia russelli, N. naja, Echis carinatus and Bungarus caeruleus) and showed limited formation of immunocomplexes with antivenom from one manufacturer. DISCUSSION: The turbidity test provides an easy and rapid way to compare and characterise interactions between antivenoms and snake venoms.

Oxycodone overdose causes naloxone responsive coma and QT prolongation.

BACKGROUND: Although there are limited data on oxycodone overdose, it has been suggested that, in addition to central nervous system (CNS) depression, oxycodone may cause QT prolongation. Given the high prescription rate and increasing use of oxycodone, an understanding of its effects and treatment in overdose is necessary. AIM: To investigate the clinical features, electrocardiogram (ECG) parameters and treatment of oxycodone overdose. DESIGN: Retrospective review of a clinical database. METHODS: One hundred and thirty-seven oxycodone overdoses were identified from admissions to a toxicology unit between January 2001 and May 2011. Demographic information, details of ingestion, clinical effects, ECG parameters [heart rate (HR), QT and QRS], naloxone use and length of stay (LOS) were extracted from a clinical database. QT was measured manually and plotted on a QT nomogram. LOS was extracted for all overdoses over the same period. RESULTS: From 137 oxycodone overdoses, 79 (58%) ingested immediate release (IR) and 58 (42%) ingested sustained release (SR) or a combination of IR and SR. The median age was 40 years [interquartile range (IQR): 33-49 years], and 87 were female (64%). The median ingested dose of IR oxycodone was 70 mg (IQR: 40-100, range: 5-200), compared to 240 mg (IQR: 80-530, range: 30-1600) for SR oxycodone. Benzodiazepines were the most frequent co-ingested drug in 52 (38%) cases. No arrhythmias were recorded. Twenty-four patients (18%) had bradycardia of which five had a HR < 50 beats/min. From 116 available ECGs, the median QRS was 95 ms (IQR: 90-102 ms), and there were 20 (17%) abnormal QT-HR pairs. Naloxone boluses were required in 65 admissions (47%), and 34 (25%) required a naloxone infusion. There was higher overall naloxone use with SR and IR + SR (32/58, 55%) compared to IR oxycodone (33/79, 42%). The median LOS was 18 h (IQR: 12-35), which was greater than the median LOS for all toxicology admissions at 15 h (IQR: 8-24) over the same period. Patients requiring a naloxone infusion had an even greater LOS of 36 h (IQR: 20-62 h). CONCLUSION: In addition to the expected CNS depression, the opioid oxycodone can cause bradycardia and QT prolongation in overdose. The SR formulation is associated with the use of naloxone infusions and a longer LOS.

Thrombotic microangiopathy in two tiger snake envenomations.

Thrombotic microangiopathies are a rare group of disorders with features such as microangiopathic haemolytic anaemia, thrombocytopenia and renal failure. Thrombotic microangiopathy has been previously reported in association with envenomation from a number of snake species. We present the first two reported cases of thrombotic microangiopathy caused by envenomation from the common tiger snake (Notechis scutatus). Both patients had classical features of thrombotic microangiopathy with microangiopathic haemolytic anaemia, thrombocytopenia and renal failure commencing in the first 48 hours after envenomation. The presentations and recovery were similar to case presentations of other snakebite envenomation associated thrombotic microangiopathies. Normal ADAMTS13 activity suggests that plasmapharesis may not be beneficial, although this needs further investigation.